Chen et al. BMC Infectious Diseases (2017) 17:441 DOI 10.1186/s12879-017-2555-x RESEARCH ARTICLE Open Access Clinical characteristics of acute hepatitis A outbreak in Taiwan, 2015–2016: observations from a tertiary medical center Nan-Yu Chen1, Zhuo-Hao Liu2, Shian-Sen Shie1, Tsung-Hsing Chen3 and Ting-Shu Wu1* Abstract Background: Acute hepatitis A is a fecal-oral transmitted disease related to inadequate sanitary conditions. In addition to its traditional classification, several outbreaks in the men who have sex with men (MSM) population have resulted in acute hepatitis A being recognized as a sexually transmitted disease. However, few studies have clarified the clinical manifestations in these outbreaks involving the MSM population. Methods: Beginning in June 2015, there was an outbreak of acute hepatitis A involving the MSM population in Northern Taiwan. We conducted a 15-year retrospective study by recruiting 207 patients with the diagnosis of acute hepatitis A that included the pre-outbreak (January 2001 to May 2015) and outbreak (June 2015 to August 2016) periods in a tertiary medical center in Northern Taiwan. Using risk factors, comorbidities, presenting symptoms, laboratory test results and imaging data, we aimed to evaluate the clinical significance of acute hepatitis A in the MSM population, where human immunodeficiency virus (HIV) coinfection is common. Results: There was a higher prevalence of reported MSM (p < 0.001), HIV (p < 0.001) and recent syphilis (p < 0.05) coinfection with acute hepatitis A during the outbreak period. The outbreak population had more prominent systemic symptoms, was more icteric with a higher total bilirubin level (p < 0.05) and had a 7-times higher tendency (p < 0.05) to have a hepatitis A relapse. Conclusions: The clinical course of acute hepatitis A during an outbreak involving the MSM and HIV-positive population is more symptomatic and protracted than in the general population. Keywords: Acute hepatitis A, HIV infection, Men who have sex with men, Male homosexual, Outbreak Background been recognized due to several reported outbreaks Acute hepatitis A is a fecal-oral transmitted disease re- among men who have sex with men (MSM) since the lated to inadequate hygienic and sanitary conditions. In 1990s [2–5]. Previous studies have linked acute hepatitis developed countries, through the elevation of public A to certain risk factors [2, 6–8], including oral-anal sex- health standards, hepatitis A has become an imported ual practices and intravenous drug use. However, the im- disease related to travel to endemic countries. Thus, pact of acute hepatitis A on high-risk populations, studies have shown decreases in antibody seroprevalence particularly the MSM population and those with pre- against hepatitis A in developed countries [1], which existing human immunodeficiency virus (HIV) infec- may also suggest that a large portion of the population is tions, has not yet been clarified. at risk should a hepatitis A outbreak occur. In addition Acute hepatitis A was endemic in Taiwan before 1995 to the traditional transmission route, the role of acute and has been a notifiable disease according to the hepatitis A as a sexually transmitted disease (STD) has Centers of Disease Control (CDC), Taiwan, since 1999 [9]. Since June 1995, when efforts in public health and * Correspondence: [email protected] the free vaccination program for children in 30 indigen- 1Division of Infectious Diseases, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 5 ous townships were initiated, annual hepatitis A cases Fuhsing Street, Kueishan, Taoyuan 333, Taiwan have declined from 2.96/100,000 in 1995 to 0.9/100,000 Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Chen et al. BMC Infectious Diseases (2017) 17:441 Page 2 of 7 in 2003–2008 [9]. Since then, acute hepatitis A has be- Recent travel was defined by domestic or international come a disease mainly related to international travel, visits within 2 months before the diagnosis of acute and the estimated seroprevalence against hepatitis A has hepatitis A was made. Close contact was defined as liv- decreased to less than 10% in those under the age of 20 ing with a confirmed acute hepatitis A case or a person according to the 2011 epidemiologic surveillance [10]. having symptoms or signs of acute hepatitis A in the This population is particularly vulnerable to an acute same household/dormitory or working/studying/in a re- hepatitis A outbreak. According to the CDC, Taiwan, lationship with a symptomatic person or a confirmed there has been an acute hepatitis A outbreak (serotype acute hepatitis A case. A recently active syphilis infec- IA) in Northern Taiwan since June 2015, notably involv- tion was defined as a 4X rise in rapid plasma reagin ing the MSM population, with half of the cases also be- (RPR)/venereal disease research laboratory (VDRL) test ing infected with HIV [11]. According to the literature, titer or if the patient received benzathine penicillin treat- only a few studies have attempted to describe acute ment for syphilis within 6 months of the acute hepatitis hepatitis A in MSM or HIV-infected populations [12, 13]. A event. In this study, a relapse was arbitrarily defined By the time this manuscript is submitted, more acute as a more than 0.5X normal upper limit elevation of ei- hepatitis A cases will have been reported. The aim of ther aspartate aminotransferase (AST) or alanine amino- this study was to explore the risk differential between transferase (ALT) during the convalescence phase before the outbreak and sporadic cases in the pre-outbreak liver function normalized. period, which may contribute to our understanding of acute hepatitis A involving the MSM and HIV- Statistical analyses positive populations. Analyses were conducted using SigmaPlot 12.0 (Systat Software, Inc., San Jose, California, USA). The differ- Methods ences between groups (before the outbreak and during This retrospective study was approved by the Institutional the outbreak) were tested for significance using the Review Board at Chang Gung Medical Foundation in Mann-Whitney Rank Sum test and Pearson’s chi-square Taiwan (approval number: 201600805A3). We conducted test for numerical variables and categorical variables, re- a 15-year retrospective, single-center study at Chang Gung spectively. Values were reported as the median and Memorial Hospital, a tertiary hospital in Northern Taiwan. ranges, and p value of less than 0.05 was considered sig- All patients with a positive or equivocal hepatitis A virus nificant for all statistical tests. (HAV) immunoglobulin M (IgM) level detected by either an enzyme-linked immunosorbent assay (ELISA) or a Results radioisotope assay between January 2001 through August Between June 2015 and August 2016, while Northern 2016 were reviewed for the presence of elevated liver en- Taiwan was experiencing a hepatitis A outbreak, a simi- zymes and symptoms/signs of hepatitis. A case was de- lar trend was detected at Chang Gung Memorial fined as having acute hepatitis A when there was positive/ Hospital (Fig. 1). The number of acute hepatitis A cases equivocal HAV IgM together with elevated liver enzymes. increased from 2 to 18 cases/year to 36 cases in 2016 Two hundred and sixty-four cases were collected. (until Aug 2016). Throughout these 15 years, males Twenty-four cases with unavailable/incomplete medical often had a stronger association with acute hepatitis A records and 10 cases that came for a health re-check after (male/total cases ratio ranging from 36.4 to 84.6%), with an acute hepatitis A episode treated elsewhere were ex- a female predominance observed only in 2001 and 2006. cluded. Twenty-three patients with an alternative diagno- The male predominance in acute hepatitis A was further sis or severe clinically confronting diseases were further exaggerated during the outbreak (male/total cases ratio excluded (Additional file 1). of 85.7% in 2015 and 91.7% in 2016), reaching statistical A total of 207 acute hepatitis A cases were collected significance (p < 0.001, Table 1). As shown in the patient and divided into the following two groups: 163 cases in demographic and risk factor analysis (Table 1), recent the pre-outbreak period (January 2001 to May 2015) and travel (56/207, 29.4%), particularly international travel- 44 cases in the outbreak period (June 2015 to August ling (37/56, 66%), was the most often reported factor 2016), as the first case of this national acute hepatitis A among pre-outbreak cases. Conversely, the most fre- outbreak was reported in June 2015 according to a state- quently reported risk factor for outbreak cases was ment by the CDC, Taiwan. Clinical manifestations, la- MSM or HIV infection (40.9%), although recent travel boratory abnormalities, image findings and treatment was still reported in a minority of cases (18.2%). Notably, outcomes were compared between these two groups. during the outbreak, there were also more cases reported The HIV infection status was defined by standard ELISA to have close contact to a confirmed acute hepatitis A case and Western blotting methods or if the patient was or a person having symptoms or signs of acute hepatitis already on combination antiretroviral therapy (cART).